During his studies at the Saint-Luc Institute in Brussels (1975–1977), François Schuiten met Claude Renard, who led the comics department at the school. Together they created several books. Schuiten's brother Luc also worked with him several times as a writer for the series Terres Creuses.

François Schuiten published his first comic on 3 May 1973 AD, consisting of 5 black and white pages in the French magazine Pilote; four years later he was published in the more experimental magazine Métal Hurlant 1).

His love of architecture became apparent in the series Cities of the Fantastic, an evocation of fantastic, partly imaginary cities that François Schuiten created with his friend Benoît Peeters from 1983 AD for the Belgian monthly comics magazine (À Suivre). Every story focuses on one city or building, and further explores a world where architects, urbanists, and ultimately “urbatects”, are the leading powers and architecture is the driving force behind society. Styles explored in the series include stalinistic and fascist architecture in La Fièvre d'Urbicande, skyscrapers in Brüsel, but also the gothic cathedrals in La Tour.2) This fascination with architecture and the possible and impossible cities it can generate is further explored in The Gates of the Possible, a weekly series Schuiten created for the newspapers Le Soir and De Morgen in 2005 AD.

Inspired by artists and scientists alike, Schuiten's work can be considered to mix the mysterious worlds of René Magritte, the early scientific fantasies of Jules Verne, the graphical worlds of M. C. Escher and Gustave Doré, and the architectural visions of Victor Horta and Étienne-Louis Boullée. 3) The creative synergy between Schuiten's work and the books of Jules Verne culminated in 1994 when he was asked to illustrate and design a cover for the publication of Verne's rediscovered book Paris in the Twentieth Century.

François Schuiten also collaborated with Maurice Benayoun on the computer graphics series Quarxs, and worked as a production designer for a few movies: Gwendoline by Just Jaeckin, Toto le héros by Jaco Van Dormael, Taxandria by Raoul Servais, The Golden Compass by Chris Weitz, and Mr. Nobody by Jaco Van Dormael. He is currently working on other feature films, such as Mars et Avril by Martin Villeneuve,4) as well as on a computer-animated film which he will co-direct with his colleague Benoît Sokal.

As a scenographer, François Schuiten designed the metro stations of Porte de Hal in Brussels and Arts et Métiers in Paris, and a mural in Brussels. In 2000 AD, he designed the scenography for A planet of visions, one of the main pavilions of the Hannover World's Fair, which attracted more than five million visitors. In 2004-2005, a large exhibition was held in Leuven, The Gates of Utopia, showing different aspects of his work. He also created the interior of the Belgian pavilion at the Expo 2005 in Aichi, Japan with the painter Alexandre Obolensky. François Schuiten has also designed 15 Belgian stamps.